Cognitive Stability Among Plasma p-tau 181 Negative Individuals: A 5-year Analysis of the Multidomain Alzheimer Prevention Trial Study

BACKGROUND: This study aims to assess the evolution of cognitive performances over a 5-year follow-up period in community-dwelling older people with negative plasma p-tau181 levels and to determine whether frailty could discriminate between those who experience cognitive decline and those who do not, in the p-tau negative groups. METHODS: This is a 5-year analysis of the Multidomain Alzheimer Prevention Trial (MAPT) testing cognitive evolution among 503 community-dwelling individuals with available data on plasma p-tau181. Negative p-tau status was assigned according to 3 different cut-offs: amyloid-PET positivity (9.6 pg/mL), highest tertile for baseline p-tau181 distribution (10.9 pg/mL), and Alzheimer's disease diagnosis prediction (12.4 pg/mL) cut-offs. Cognition was measured using a validated composite cognitive score derived from the Z-scores of 4 cognitive tests. Longitudinal changes from baseline in the composite cognitive score according to plasma p-tau181 status were compared using linear mixed models. RESULTS: In a population with an end-of-study median age of 79 years (interquartile range: 76-82), whatever the cut-off, the overall group with negative p-tau181 status did not develop cognitive decline over the follow-up. Among the p-tau181 negative groups, individuals who declined had a higher prevalence of frailty compared to those who did not decline. CONCLUSIONS: Cognitive performance in older people with negative plasma p-tau181 levels remains stable over a 5-year period. This may suggest that older age alone, in the absence of positive biomarkers for brain pathology (or frailty), is not associated with cognitive decline. Frailty may increase vulnerability to the neuropathological burden associated with Alzheimer's disease.